CN113754619B - A kind of ruthenium catalyzes the method for preparing multi-substituted benzofuran-4-carboxylic acid compounds - Google Patents

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a method for preparing a polysubstituted benzofuran-4-formic acid compound under the catalysis of ruthenium. Heating m-hydroxybenzoic acid compound, diaryl alkyne compound, ruthenium catalyst, additive and solvent in air or oxygen environment for reaction, separating and purifying reaction products to obtain polysubstituted benzofuran-4-formic acid compound. The high catalytic activity of the ruthenium catalyst system used in the method of the invention enables the reaction to use air or oxygen as a green oxidant, avoiding the use of toxic, dangerous or expensive oxidants. The reaction raw materials are easy to obtain, the solvent amount is small, the reaction is not sensitive to water, the operation is simple, convenient and safe, the reaction can be well amplified to gram-scale, and the industrialization is convenient to realize. The reaction of the invention is taken as a key step, the natural product dipterondsesin G with bioactivity can be conveniently synthesized, and the invention has good application prospect.

Description

A kind of ruthenium catalyzes the method for preparing multi-substituted benzofuran-4-carboxylic acid compounds

technical field

The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing polysubstituted benzofuran-4-carboxylic acid compounds by ruthenium catalysis.

Background technique

Multi-substituted benzofurans widely exist in natural products, bioactive molecules and drug molecules, and their efficient synthesis methods have broad application prospects [(a) Keylor M.H., Matsuura B.S., StephensonC.R.J.Chem.Rev.2015,115, 8976; (b) Heravi M.M., Zadsirjan V., Hamidi H., Amiri P.H.T. RSC Adv.2017, 7, 24470; (c) Miao, Y.-h.; Hu, Y.-h.; Yang, J .; Liu, T.; Sun, J.; Wang, X.-j. RSC Adv.2019, 9, 27510.]. Among them, 2,3-diarylbenzofuran is the core skeleton of a large class of biologically active natural products, and is also a key intermediate for the synthesis of these natural products and their analogs (Keylor M.H., Matsuura B.S., Stephenson C.R.J.Chem. Rev. 2015, 115, 8976). For example, diptoindonesin G can be used as an immunosuppressant, has anti-tumor cell proliferation activity, and can also selectively regulate estrogen receptors [(a) GeH.M., Yang W.H., Shen Y., et al.Chem.Eur. J. 2010, 16, 6338; (b) Zhao Z., Wang L., James T., et al. Chem. Biol. 2015, 22, 1608; (c) Gao J., Fan M., Xiang G., et al. Cell Death Dis. 2017, 8, e2765.]. Recent studies have shown that diptoindonesin G has a significant effect on inhibiting the proliferation of breast cancer cells, and it is expected to become a leading drug for the treatment of breast cancer (Fan M., Chen J., Gao J., et al. Cell Death Dis. 2020, 11, 635). There are many other natural products containing multiple substituted benzofuran skeletons, such as viniferifuran, malibatolA, shoreaphenol and rhamnoneuronal C, etc., all of which have good biological activities.

Based on the important biological activities of the above-mentioned natural products and their prospects in drug development, their total synthesis and analogue synthesis have attracted much attention, among which polysubstituted benzofuran-4-carboxylic acid and its derivatives are the key to the synthesis of such natural products Intermediate [(a) Kim I., Choi J.Org.Biomol.Chem.2009, 7, 2788; (b) Kim K., KimI.Org.Lett.2010, 12, 5314; (c) Vo D.D., Elofsson M.Adv.Synth.Catal.2016,358,4085; (d) Liu J.-t., Do T.J., Simmons C.J., et al.Org.Biomol.Chem.2016,14,8927; (e) SinghD .K., Kim I.J.Org.Chem.2018,83,1667.]. However, the reported synthetic routes require multi-step reactions from complex raw materials and are not universally applicable. The efficient synthesis of multi-substituted benzofuran-4-carboxylic acids from simple and easy-to-obtain raw materials needs to be further developed.

Alkyne cyclization of phenols is an efficient strategy for the synthesis of diarylbenzofurans. In 2013, Sahoo et al. reported that phenols and diaryl alkynes were activated by carbon-hydrogen bonds under palladium-catalyzed conditions to obtain benzofurans (Kuram M.R., Bhanuchandra M., Sahoo A.K.Angew.Chem.Int.Ed.2013,52, 4607). Since then, copper-catalyzed, rhodium-catalyzed, gold-catalyzed, or zinc chloride-promoted reaction systems have been gradually developed for the synthesis of benzofurans via the cyclization of phenols and alkynes [(a) Zhu R.Y., Wei J.B., Shi Z.J.Chem. Sci.2013,4,3706; (b) Zeng W., Wu W.Q., JiangH.F., et al.Chem.Commun.2013,49,6611; (c) Yeh C.-H., Chen W.- C., Gandeepan P., etal.Org.Biomol.Chem.2014, 12, 9105; (d) Liao J., Guo P., Chen Q.Catal.Commun.2016, 77, 22; (e) Sreenivasulu C ., Reddy A.G.K., Satyanarayana G.Org.Chem.Front.2017, 4, 972]. However, no ruthenium-catalyzed synthesis of benzofuran rings through the reaction of phenols and alkynes has been reported. In addition, none of the above synthetic techniques are suitable for the synthesis of carboxybenzofurans. In the reported reaction system, when hydroxybenzoic acid is used as a substrate for carbon-hydrogen bond activation and alkyne cyclization reaction, hydroxyisocoumarin or naphthol products will be generated, but carboxybenzofuran compounds cannot be obtained[ (a) Ueura K., Satoh T., Miura M. J. Org. Chem. 2007, 72, 5362; (b) Ackermann L., Pospech J., Graczyk K., et al. Org. Lett. 2012, 14, 930; (c) Hirosawa K., Usuki Y., Satoh, T. Adv. Synth. Cat. 2019, 361, 5253; (d) Sihag P., Jeganmohan, M.J. Org. Chem. 2019, 84, 2699.].

Contents of the invention

In view of the above shortcomings and deficiencies in the prior art, the object of the present invention is to provide a method for preparing multi-substituted benzofuran-4-carboxylic acid compounds by ruthenium catalysis. The method uses m-hydroxybenzoic acid compounds as raw materials, reacts with diarylphenylacetylene under the catalysis of ruthenium, and obtains multi-substituted 2,3-diarylbenzene through a series of carbon-hydrogen bond enylation and oxidative cyclization reactions And furan-4-carboxylic acid compounds. The method uses air or oxygen as an oxidizing agent, has simple and easy-to-obtain raw materials, convenient reaction operation and wide applicability. Taking this method as a key step, the biologically active natural product diptoindonesin G can be conveniently synthesized, which has a good application prospect.

The purpose of the present invention is achieved through the following technical solutions.

A method for preparing multi-substituted benzofuran-4-carboxylic acid compounds by ruthenium catalysis, comprising the following preparation steps: m-hydroxybenzoic acid compound (I), diaryl alkyne (II), ruthenium catalyst, additive and solvent Add to a reaction vessel, heat and stir the reaction under air or oxygen environment, the reaction crude product is separated and purified to obtain polysubstituted benzofuran-4-carboxylic acid products (III) and (IV), the reaction formula is as formula (1).

Wherein, R ¹ , R ² and R ³ are each independently selected from hydrogen, C ₁ -C ₈ alkyl, C ₆ -C ₁₀ aryl, C ₁ -C ₈ alkoxy, benzyloxy, halogen, trifluoro One of methyl, hydroxyl, carboxyl, ester; Ar ¹ and Ar ² are relatively independently substituted or unsubstituted aryl; when Ar ² = Ar ¹ , the diaryl alkyne is a symmetrical diaryl Alkyne (V) to obtain multi-substituted benzofuran-4-formic acid product (VI), the reaction formula is as shown in formula (2);

Preferably, the diaryl alkyne (II) has the following structure (VII):

Wherein, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from hydrogen, C ₁ -C ₈ alkyl, C ₆ -C ₁₀ One of aryl, C ₁ -C ₈ alkoxy, benzyloxy, halogen, trifluoromethyl, trifluoromethoxy, ester group.

The ruthenium catalyst is at least one of a divalent ruthenium complex, a trivalent ruthenium complex, a divalent ruthenium salt, and a trivalent ruthenium salt; preferably, the ruthenium catalyst is selected from p-cymene dichloride ruthenium dichloride Polymer, phenyl ruthenium dichloride dimer, ruthenium trichloride, ruthenium trichloride hydrate, three (triphenylphosphine) ruthenium dichloride, ruthenium acetate; more preferably p-cymene Ruthenium dichloride dimer.

The additive is an alkaline or chlorine-containing ionic additive; preferably, the additive is magnesium acetate tetrahydrate, magnesium acetate anhydrous, calcium acetate monohydrate, calcium acetate anhydrous, lithium acetate, sodium acetate, potassium acetate, One of guanidine carbonate and magnesium chloride; more preferably magnesium acetate tetrahydrate.

The solvent is a polar aprotic solvent; preferably, the solvent is a high-boiling polar aprotic solvent, more preferably γ-valerolactone (GVL).

Preferably, the molar ratio of the diaryl alkyne (II) to the m-hydroxybenzoic acid compound (I) is 1:(0.8-2); more preferably 1:1.2.

Preferably, the molar dosage of the catalyst satisfies: 1%-10% of the molar dosage of the diaryl alkyne (II) based on the amount of metal ruthenium contained; more preferably 3%-5%.

Preferably, the molar amount of the additive is 10%-60% of the molar amount of the diaryl alkyne (II); more preferably 15%-30%.

Preferably, the amount of the solvent is 0.5-5 mL of solvent per 1 mmol of diaryl alkyne (II); more preferably 1-1.5 mL of solvent per 1 mmol of diaryl alkyne (II).

Preferably, the heating reaction refers to the reaction at 90-120°C for 6-30 hours; more preferably, the reaction at 100°C for 10-24 hours.

Preferably, the separation and purification refers to cooling the resulting reaction solution to room temperature, adding ethyl acetate to dilute, filtering through a thin layer of diatomaceous earth, adding saturated sodium chloride or ammonium chloride solution, and extracting with ethyl acetate. After drying and concentrating, it is separated by silica gel column chromatography, rotary evaporated and sucked dry to obtain the purified product.

The principle of the present invention is: under ruthenium catalysis, carbon-hydrogen bond activation occurs at the position between the carboxyl group and the hydroxyl group in the m-hydroxybenzoic acid compound, and then adds to the diaryl alkyne, and the alkenylated intermediate product generated is further An oxidative cyclization reaction occurs to obtain polysubstituted benzofuran-4-carboxylic acid compounds. In the reaction, the carboxyl group acts as a guiding group to assist ruthenium to activate the carbon-hydrogen bond, and the hydroxyl group also assists the carbon-hydrogen bond functionalization process and participates in the construction of the furan ring, and the additive can promote the reaction.

Compared with the prior art, the present invention has the following advantages and beneficial effects:

(1) The m-hydroxybenzoic acid compounds and diaryl alkynes used in the inventive method are chemical raw materials with a wide range of sources, and the ruthenium catalyst used can be directly bought, and is relatively cheap among noble metal catalysts.

(2) The present invention uses air or oxygen as a green oxidant, avoiding the use of toxic, dangerous or expensive oxidants, the by-product is only water, the reaction operation is convenient and safe, no special experimental equipment or water and oxygen removal operations are required, and it can be enlarged to The gram-level scale is convenient for industrialization.

(3) The reaction involved in the method of the present invention is compatible with multiple functional groups, and has good selectivity to most of the substrates. The resulting product can be used for the efficient synthesis of the biologically active natural product diptoindonesin G, and can also be used for the synthesis of several other benzos Furan natural products have good application prospects.

Description of drawings

Figure 1 is a single crystal structure diagram of the product obtained in Example 1.

Fig. 2 is the proton nuclear magnetic spectrum figure of the product obtained in embodiment 9.

Fig. 3 is the proton nuclear magnetic spectrum figure of the product obtained in embodiment 10.

Fig. 4 is the proton nuclear magnetic spectrum figure of the product obtained in embodiment 13.

Fig. 5 is the proton nuclear magnetic spectrum figure of the product obtained in embodiment 15.

Fig. 6 is the proton nuclear magnetic spectrum figure of the product obtained in embodiment 18.

Fig. 7 is the proton nuclear magnetic spectrum figure of the product obtained in embodiment 19.

Fig. 8 is the NMR spectrum of the product obtained in Example 24.

Fig. 9 is the nuclear magnetic hydrogen spectrogram of the product obtained in embodiment 28.

FIG. 10 is a single crystal structure diagram of the product 3-(4-chlorophenyl)-2-(4-methoxyphenyl)-6-methylbenzofuran-4-carboxylic acid obtained in Example 33.

Fig. 11 is the obtained product 3-(3,5-dimethoxyphenyl)-6-methoxy-2-(4-methoxyphenyl)-benzofuran-4-carboxylic acid in embodiment 34 H NMR spectrum.

Figure 12 is the H NMR spectrum of the product diptoindonesin G obtained in Example 35.

detailed description

The present invention will be further described in detail below in conjunction with the embodiments and the accompanying drawings, but the embodiments of the present invention are not limited thereto. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.

The reagents used in the examples can be routinely purchased from the market unless otherwise specified.

Example 1

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), toluene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then stir at 100 ° C React for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (95.7mg, yield 73%) which is the product 6-methyl-2,3-di Phenylbenzofuran-4-carboxylic acid.

The structure of the obtained product is determined by nuclear magnetic hydrogen spectrum and carbon spectrum, high-resolution mass spectrum and single crystal X-ray diffraction analysis. ¹ H NMR (600MHz, CDCl ₃ ) δ7.55–7.50(m,4H),7.38–7.36(m,2H),7.34–7.31(m,3H),7.25–7.22(m,3H),2.51(s ,3H)； ¹³ C NMR(151MHz,CDCl ₃ )δ172.03,154.96,152.33,134.45,134.33,130.55,130.15,128.52,128.43,128.39,127.53,127.15,126.82,126.51,123.83,118.07,115.64,21.53；HRMS (ESI) calcd for C ₂₂ H ₁₆ O ₃ [MH] ^- 327.1027, found 327.1027. The single crystal structure of the product is shown in Figure 1.

Example 2

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), toluene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch to connect to the oxygen balloon, and then at 100 ° C The reaction was stirred for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (93.5 mg, yield 71%) which is the product 6-methyl-2,3-di Phenylbenzofuran-4-carboxylic acid.

Example 3

In a 10mL reaction tube with a branch, add a magnetic stirrer, hydrated ruthenium trichloride (0.016mmol, 3.3mg), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), toluene ( 71.3mg, 0.4mmol), anhydrous magnesium acetate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave the branch open to the air, then stir and react at 100°C for 24 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (76.0 mg, yield 58%) which is the product 6-methyl-2,3-di Phenylbenzofuran-4-carboxylic acid.

Example 4

Into a 10mL reaction tube with a branch, add a magnetic stirrer, ruthenium acetate (0.016mmol, 4.5mg), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol), toluene (71.3mg, 0.4mmol), magnesium chloride (3.8mg, 0.04mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave the branch open to the air, then stir and react at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (67.4 mg, yield 51%) which is the product 6-methyl-2,3-di Phenylbenzofuran-4-carboxylic acid.

Example 5

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 5-hydroxy-2-methylbenzoic acid (73.2mg, 0.48mmol ), toluene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then stir at 100 ° C React for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (106.7 mg, yield 81%) which is the product 5-methyl-2,3-di Phenylbenzofuran-4-carboxylic acid.

Example 6

First, the starting material 3-butyl-5-hydroxybenzoic acid was prepared using literature method (Sun H.-X., Sun Z.-H., Wang B. Tetrahedron Lett. 2009, 50, 1596.). In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-butyl-5-hydroxybenzoic acid (93.2mg, 0.48mmol ), toluene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then stir at 100 ° C React for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (102.1 mg, yield 69%) which is the product 6-butyl-2,3-di Phenylbenzofuran-4-carboxylic acid.

Example 7

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-phenyl-5-hydroxybenzoic acid (102.8mg, 0.48mmol ), toluene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then stir at 100 ° C React for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (110.4 mg, yield 71%) which is the product 2,3,6-triphenylbenzene And furan-4-carboxylic acid.

Example 8

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methoxybenzoic acid (80.7mg, 0.48 mmol), diphenylacetylene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, and then in 100 ℃ The reaction was stirred for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry to obtain a white solid (107.5 mg, yield 78%) which is the product 6-methoxy-2,3- Diphenylbenzofuran-4-carboxylic acid.

Example 9

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-4,5-dimethoxybenzoic acid (95.1 mg, 0.48mmol), diphenylacetylene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then in The reaction was stirred at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, separated by silica gel column chromatography, rotary evaporation and pumping to dryness, a white solid (85.7 mg, yield 57%) was obtained as the product 6,7-dimethoxy-2 ,3-Diphenylbenzofuran-4-carboxylic acid.

The structure of the obtained product was determined by H NMR, C NMR and high resolution mass spectrometry. ¹ H NMR (600MHz, CDCl ₃ ) δ7.50–7.47(m,2H),7.4(s,1H),7.40–7.37(m,2H),7.35–7.33(m,1H),7.33–7.31(m ,2H),7.25–7.26(m,3H),4.38(s,3H),4.0(s,3H); ¹³ C NMR(151MHz,CDCl ₃ )δ170.65,152.73,147.59,146.05,138.09,134.39,130.36, 130.16, 128.61, 128.47, 128.39, 127.53, 127.07, 126.10, 118.19, 116.40, 112.55, 61.25, 57.35; HRMS (ESI) calcd for C ₂₃ H ₁₈ O ₅ [MH] ^- 373.1081, found 373.108273. The H NMR spectrum of the product is shown in Figure 2.

Example 10

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-benzyloxy-5-hydroxybenzoic acid (117.2mg, 0.48 mmol), diphenylacetylene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, and then in 100 ℃ The reaction was stirred for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (110.8 mg, yield 66%) which is the product 6-benzyloxy-2,3- Diphenylbenzofuran-4-carboxylic acid.

The structure of the obtained product was determined by H NMR, C NMR and high resolution mass spectrometry. ¹ H NMR (600MHz, CDCl ₃ ) δ7.50–7.47(m,4H),7.44–7.41(m,3H),7.38–7.30(m,7H),7.26–7.23(m,3H),5.19(s ,2H)； ¹³ CNMR(151MHz,CDCl ₃ )δ170.86,156.27,155.57,152.13,136.55,134.40,130.55,130.14,128.86,128.45,128.42,128.38,128.35,127.67,127.59,126.91,124.33,122.83,117.99, 114.75, 101.47, 70.98; HRMS (ESI) calcd for _C28H20O4 [MH] ^- _419.1289 , found _419.1292 . The H NMR spectrum of the product is shown in Figure 3.

Example 11

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-chloro-5-hydroxybenzoic acid (82.8mg, 0.48mmol) , toluene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then stir the reaction at 100 ° C 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (83.4 mg, yield 60%) which is the product 6-chloro-2,3-diphenyl benzofuran-4-carboxylic acid.

Example 12

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-bromo-5-hydroxybenzoic acid (104.2mg, 0.48mmol) , toluene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then stir the reaction at 100 ° C 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry to obtain a white solid (95.1 mg, yield 61%) which is the product 6-bromo-2,3-diphenyl benzofuran-4-carboxylic acid.

Example 13

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 2-fluoro-5-hydroxybenzoic acid (74.9mg, 0.48mmol) , toluene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then stir the reaction at 100 ° C 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (70.2 mg, yield 53%) which is the product 5-fluoro-2,3-diphenyl benzofuran-4-carboxylic acid.

The structure of the obtained product was confirmed by H NMR, C NMR, F NMR, and high resolution mass spectrometry. ¹ H NMR (600MHz, DMSO-d ₆ ) δ 13.17 (brs, 1H), 7.82 (dd, J=8.9, 3.7Hz, 1H), 7.49–7.44 (m, 5H), 7.36–7.30 (m, 6H ); ¹³ C NMR (151MHz, DMSO-d ₆ ) δ164.17, 154.91 (d, J=239.8Hz), 152.73, 149.41, 131.29, 130.00, 129.29, 129.18, 128.71, 128.70, 128.23, 126.55 (d, J=7.2 Hz), 117.67(d, J=3.9Hz), 115.28(d, J=22.1Hz), 113.39(d, J=10.0Hz), 112.76(d, J=26.6Hz); ¹⁹ F NMR (565MHz, DMSO -d ₆ ) δ - 123.93; HRMS (ESI) calcd for C ₂₁ H ₁₃ O ₃ F[MH] ^- 331.0776, found 331.0777. The H NMR spectrum of the product is shown in Figure 4.

Example 14

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 2-chloro-5-hydroxybenzoic acid (82.8mg, 0.48mmol) , toluene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then stir the reaction at 100 ° C 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry to obtain a white solid (81.2 mg, yield 58%) which is the product 5-chloro-2,3-diphenyl benzofuran-4-carboxylic acid.

Example 15

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-trifluoromethyl-5-hydroxybenzoic acid (98.9mg, 0.48mmol), diphenylacetylene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then at 100 ° C The reaction was stirred for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (82.4 mg, yield 55%) which is the product 2,3-diphenyl-6- Trifluoromethylbenzofuran-4-carboxylic acid.

The structure of the obtained product was confirmed by H NMR, C NMR, F NMR, and high resolution mass spectrometry. ¹ H NMR (600MHz, CD ₃ OD) δ7.93(m,1H),7.74(m,1H),7.38–7.36(m,2H),7.32–7.30(m,3H),7.20–7.17(m, 3H),7.15–7.13(m,2H); ¹³ C NMR(151MHz,CD ₃ OD)δ169.05,156.61,155.05,134.52,131.85,131.27,130.72,130.44,129.61,129.47,128.95,128.703,128 q, J=33.2Hz), 125.53(q, J=271.1Hz), 122.21(q, J=3.8Hz), 119.27, 112.16(q, J=3.9Hz); ¹⁹ F NMR(565MHz, CD ₃ OD) δ - 62.73; HRMS (ESI) calcd for C ₂₂ H ₁₃ O ₃ F ₃ [MH] ^- 381.0744, found 381.0743. The H NMR spectrum of the product is shown in Figure 5.

Example 16

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3,5-dihydroxybenzoic acid (74.0mg, 0.48mmol), Diphenylacetylene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then stir the reaction at 100°C for 20 Hour. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated ammonium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry to obtain a white solid (70.8 mg, yield 54%) which is the product 6-hydroxy-2,3-diphenyl benzofuran-4-carboxylic acid.

Example 17

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3,5-dihydroxy-4-methylbenzoic acid (80.7mg , 0.48mmol), toluene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, and then at 100 The reaction was stirred at °C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated ammonium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (71.4mg, yield 52%) which is the product 6-hydroxyl-7-methyl-2 ,3-Diphenylbenzofuran-4-carboxylic acid.

Example 18

Into a 10 mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9 mg, 0.008 mmol), 4-bromo-3,5-dihydroxybenzoic acid (111.8 mg, 0.48mmol), diphenylacetylene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then at 100 ° C The reaction was stirred for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated ammonium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents, separated by silica gel column chromatography, rotary evaporated and sucked dry to obtain a white solid (63.9mg, yield 39%) which was the product 7-bromo-6-hydroxyl-2, 3-Diphenylbenzofuran-4-carboxylic acid.

The structure of the obtained product was determined by H NMR, C NMR and high resolution mass spectrometry. ¹ H NMR (600MHz, CDCl ₃ ) δ7.45–7.46(m,2H), 7.43–7.39(m,3H), 7.32–7.30(m,2H), 7.25–7.22(m,4H); ¹³ C NMR (151MHz,CDCl ₃ )δ169.87,154.25,153.47,152.83,135.26,131.43,131.24,129.51,129.47,129.36,128.69,127.70,126.71,122.11,119.89,114.60,96.15；HRMS(ESI)calcdfor C ₂₁ H ₁₃ O ₄ Br[MH] ^- 406.9924, found 406.9925. The H NMR spectrum of the product is shown in Figure 6.

Example 19

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 5-hydroxyisophthalic acid (87.4mg, 0.48mmol), di Phenylacetylene (71.3mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave the branch open to the air, then stir and react at 100°C for 20 hours . After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated ammonium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry to obtain a white solid (57.5 mg, yield 40%) which is the product 2,3-diphenylbenzofuran -4,6-dicarboxylic acid.

The structure of the obtained product was determined by H NMR, C NMR and high resolution mass spectrometry. ¹ H NMR (600MHz, CD ₃ OD) δ8.32(d, J=1.3Hz, 1H), 8.26(d, J=1.3Hz, 1H), 7.50–7.48(m, 2H), 7.44–7.40(m ,3H),7.31–7.29(m,3H),7.27–7.24(m,2H); ¹³ C NMR(151MHz,CD ₃ OD)δ169.81,168.89,156.68,155.29,134.78,132.57,131.27,130.93,130.35, 129.58, 129.45, 128.85, 128.43, 127.86, 127.71, 126.93, 119.54, 116.15; HRMS (ESI) calcd for C ₂₂ H ₁₄ O ₅ [MH] ^- 357.0768, found 357.0767. The H NMR spectrum of the product is shown in Figure 7.

Example 20

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(4-butylphenyl)acetylene (116.2mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air , and then the reaction was stirred at 100 °C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (132.1 mg, yield 75%) which is the product 2,3-bis(4-butyl Phenyl)-6-methylbenzofuran-4-carboxylic acid.

Example 21

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(4-methoxyphenyl)acetylene (95.3mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open with air communicated, and then stirred and reacted at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (99.8 mg, yield 64%) which is the product 2,3-bis(4-methoxy phenyl)-6-methylbenzofuran-4-carboxylic acid.

Example 22

The alkyne starting material bis(4-benzyloxyphenyl)acetylene was first prepared using literature methods (Boger D.L., Boyce C.W., Labroli M.A., et al. J. Am. Chem. Soc. 1999, 121, 54.). In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(4-benzyloxyphenyl) acetylene (156.2mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open with air communicated, and then stirred and reacted at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (132.2 mg, yield 61%) which is the product 2,3-bis(4-benzyloxy phenyl)-6-methylbenzofuran-4-carboxylic acid.

Example 23

The alkyne starting material bis(2-methoxyphenyl)acetylene was first prepared using literature methods (Park K., Bae G., Moon J., et al. J. Org. Chem. 2010, 75, 6244.). In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (0.02mmol, 12.2mg), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(2-methoxyphenyl)acetylene (95.3mg, 0.40mmol), guanidine carbonate (24.2mg, 0.20mmol) and 1mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then The reaction was stirred at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated ammonium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (69.5 mg, yield 45%) which is the product 2,3-bis(2-methoxy phenyl)-6-methylbenzofuran-4-carboxylic acid.

Example 24

The alkyne starting material bis(2,4-methoxyphenyl)acetylene was first prepared using literature methods (Park K., Bae G., Moon J., et al. J. Org. Chem. 2010, 75, 6244.) . In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (0.02mmol, 12.2mg), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(2,4-methoxyphenyl)acetylene (119.3mg, 0.40mmol), guanidine carbonate (24.2mg, 0.20mmol) and 1mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air , and then the reaction was stirred at 100 °C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated ammonium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (77.3 mg, yield 43%) which is the product 2,3-bis(2,4- Methoxyphenyl)-6-methylbenzofuran-4-carboxylic acid.

The structure of the obtained product was determined by H NMR, C NMR and high resolution mass spectrometry. ¹ H NMR (600MHz, CDCl ₃ )δ7.55(s,1H),7.53(s,1H),7.23(dd,J=8.5,2.0Hz,1H),7.08(d,J=2.0Hz,1H) ,6.92–9.88(m,3H),6.79(d,J＝8.6Hz,1H),3.88(s,3H),3.87(s,3H),3.79(s,3H),3.66(s,3H); ¹³ C NMR(151MHz,CDCl ₃ )δ171.70,154.67,152.30,149.34,149.10,148.57,148.50,133.94,127.31,126.77,126.55,123.55,123.32,122.76,119.96,116.33,115.35,113.65,111.43,110.99,109.99 , 56.07, 56.05, 55.94, 55.63, 21.51; HRMS (ESI) calcd for C ₂₆ H ₂₄ O ₇ [MH] ^- 447.1449, found 447.1449. The H NMR spectrum of the product is shown in Figure 8.

Example 25

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(4-fluorophenyl)acetylene (85.7mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, The reaction was then stirred at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (102.3mg, yield 70%) which is the product 2,3-bis(4-fluorobenzene base)-6-methylbenzofuran-4-carboxylic acid.

Example 26

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (0.01mmol, 6.1mg), 3-hydroxy-5-methylbenzoic acid (36.6mg, 0.24mmol ), bis(4-bromophenyl)acetylene (49.4mg, 0.20mmol), guanidine carbonate (12.1mg, 0.10mmol) and 1mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, then in 100 The reaction was stirred at °C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated ammonium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (84.8mg, yield 87%) which is the product 2,3-bis(4-bromobenzene base)-6-methylbenzofuran-4-carboxylic acid.

Example 27

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(4-trifluoromethylphenyl)acetylene (125.7mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cap the upper opening of the reaction tube and leave its branch The air was communicated, and then the reaction was stirred at 100° C. for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (115.6 mg, yield 62%) which is the product 6-methyl-2,3-di (4-trifluoromethylphenyl)benzofuran-4-carboxylic acid.

Example 28

The alkyne starting material bis(4-trifluoromethoxyphenyl)acetylene was first prepared using literature methods [(a) Guo W., Wu S., Wang T., et al.Org.Chem.Front.2018, 5, 1613; (b) Park K., Bae G., Moon J., et al. J. Org. Chem. 2010, 75, 6244.]. In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(4-trifluoromethoxyphenyl) acetylene (138.5mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mLGVL, cover the upper opening of the reaction tube and leave its branch with The air was communicated, and then the reaction was stirred at 100° C. for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (108.7 mg, yield 55%) which is the product 6-methyl-2,3-di (4-trifluoromethoxyphenyl)benzofuran-4-carboxylic acid.

The structure of the obtained product was confirmed by H NMR, C NMR, F NMR, and high resolution mass spectrometry. ¹ H NMR (600MHz, CDCl ₃ )δ7.57(s,1H),7.50(s,1H),7.43–7.42(m,2H),7.27–7.25(m,2H),7.20–7.18(m,2H ),7.05–7.04(m,2H),2.47(s,3H); ¹³ C NMR(151MHz,CDCl ₃ )δ171.45,155.04,151.34,149.31(q,J=1.6Hz),148.90(q,J=1.7 Hz), 135.14, 133.41, 131.73, 128.91, 128.58, 127.79, 126.34, 123.39, 120.92, 120.88, 120.71(q, J=257.1Hz), 120.52(q, J=257.8Hz), 117.33, 1116.46, ² F NMR (565MHz, CDCl ₃ ) δ-57.67, -57.75; HRMS (ESI) calcd for C ₂₄ H ₁₄ O ₅ F ₆ [MH] ^- 495.0673, found 495.0672. The H NMR spectrum of the product is shown in Figure 9.

Example 29

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), dimethyl 4,4'-(acetylene-1,2-diyl)dibenzoate (117.7mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, capped for reaction Open the tube and leave its branch open to the air, then stir and react at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (103.5 mg, yield 58%) which is the product 2,3-bis(4-methoxy Carbonylphenyl)-6-methylbenzofuran-4-carboxylic acid.

Example 30

The alkyne starting material bis(3,4-methoxyphenyl)acetylene was first prepared using literature methods (Lade D.M., Pawar A.B., Mainkar P.S., et al. J. Org. Chem. 2017, 82, 4998.). In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(3,4-dimethoxyphenyl)acetylene (119.3mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cap the upper opening of the reaction tube and keep the The port was connected to the air, and then stirred and reacted at 100° C. for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (82.0 mg, yield 53%) which is the product 2,3-bis(3,4- Dimethoxyphenyl)-6-methylbenzofuran-4-carboxylic acid.

Example 31

The alkyne starting material bis(3,5-methoxyphenyl)acetylene was first prepared using literature methods (Lade D.M., Pawar A.B., Mainkar P.S., et al. J. Org. Chem. 2017, 82, 4998.). In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(3,5-dimethoxyphenyl)acetylene (119.3mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cap the upper opening of the reaction tube and keep the The port was connected to the air, and then stirred and reacted at 100° C. for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (123.9 mg, yield 69%) which is the product 2,3-bis(3,5- Dimethoxyphenyl)-6-methylbenzofuran-4-carboxylic acid.

Example 32

The alkyne starting material bis(4-methoxy-3,5-dimethylphenyl)acetylene was first prepared using a literature method (Park K., Bae G., Moon J., et al. J. Org. Chem. 2010 ,75,6244.). In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), bis(4-methoxy-3,5-dimethylphenyl)acetylene (117.8mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, capped on the reaction tube Open the mouth and leave its branch open to the air, then stir and react at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (99.7mg, yield 56%) which is the product 2,3-bis(4-methoxy -3,5-dimethylphenyl)-6-methylbenzofuran-4-carboxylic acid.

Example 33

The alkyne starting material 1-chloro-4-((4-methoxyphenyl)ethynyl)benzene was first prepared using literature methods (Wu H., Shao C., Wu D., et al. J. Org. Chem. 2021, 86, 5327.). Carry out the ruthenium-catalyzed reaction according to the following process again, and the reaction formula is shown in formula (3).

In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methylbenzoic acid (73.2mg, 0.48mmol ), 1-chloro-4-((4-methoxyphenyl)ethynyl)benzene (97.8mg, 0.4mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, capped reaction tube Open the mouth and leave its branch to communicate with the air, then stir and react at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents, separated by silica gel column chromatography, and the solutions containing the two isomers were sequentially collected, rotary evaporated and sucked dry, respectively, to obtain two solid products.

3-(4-chlorophenyl)-2-(4-methoxyphenyl)-6-methylbenzofuran-4-carboxylic acid is less polar and comes out first after passing through the column. Finally, a white solid product (50.4 mg, yield 32%) was obtained. The structure of the obtained product is confirmed by H NMR and C NMR, high resolution mass spectrum and single crystal X-ray diffraction analysis. ¹ H NMR (600MHz, CDCl ₃ ) δ7.67–7.28(m,8H), 6.85–6.84(m,2H), 3.82(s,3H), 2.56(s,3H); ¹³ C NMR (151MHz, CDCl ₃ )δ171.45,160.01,154.86,152.84,134.10,133.60,133.28,131.78,128.70,128.62,127.19,126.65,123.06,122.93,115.76,115.35,114.07,55.42,21.51；HRMS(ESI)calcd for C ₂₃ H ₁₇ O ₄ Cl [MH] ^- 391.0743, found 391.0747. The single crystal structure of the product is shown in Figure 10.

The polarity is relatively large, and the product that comes out after passing through the column is 2-(4-chlorophenyl)-3-(4-methoxyphenyl)-6-methylbenzofuran-4-carboxylic acid, which is rotary evaporated and drained Afterwards, a white solid product (73.4 mg, yield 47%) was obtained. The structure of the obtained product was determined by H NMR, C NMR and high resolution mass spectrometry. ¹ H NMR (600MHz, CDCl ₃ ) δ7.56(s, 1H), 7.53(s, 1H), 7.47(d, J=8.4Hz, 2H), 7.25–7.21(m, 4H), 6.93(d, J＝8.4Hz, 2H), 3.80(s, 3H), 2.54(s, 3H); ¹³ C NMR (151MHz, CDCl ₃ ) δ171.02, 159.26, 154.92, 151.25, 134.64, 134.40, 131.18, 129.15, 128.75, 128.24 , 126.88, 126.67, 126.28, 123.90, 118.12, 115.59, 114.14, 55.36, 21.57; HRMS (ESI) calcd for C ₂₃ H ₁₇ O ₄ Cl[MH] ^- 391.0743, found 391.0747.

Embodiment 34 (the key intermediate of synthetic natural product diptoindonesin G)

The alkyne starting material 1,3-dimethoxy-5-((4-methoxyphenyl)ethynyl)benzene was first prepared using a literature method (Jeffrey J.L., Sarpong R. Tetrahedron Lett. 2009, 50, 1969.) , and then carry out the ruthenium-catalyzed reaction according to the following process. In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methoxybenzoic acid (80.7mg, 0.48 mmol), 1,3-dimethoxy-5-((4-methoxyphenyl)ethynyl)benzene (107.3mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mLGVL , Cover the upper opening of the reaction tube and leave the branch open to the air, then stir and react at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents to separate by silica gel column chromatography to obtain a solution containing two isomers, which was dried by rotary evaporation to obtain a crude product. The crude product was recrystallized using methanol, and the mother liquor was separated by preparing a silica gel chromatographic plate using petroleum ether and ethyl acetate (1:1 mixed solution) as a developing solvent to obtain two pure products.

3-(3,5-dimethoxyphenyl)-6-methoxy-2-(4-methoxyphenyl) precipitated during recrystallization and less polar when separated on silica gel plate -Benzofuran-4-carboxylic acid, a white solid product (64.7 mg, yield 37%) was obtained after drying. The structure of the obtained product was determined by H NMR, C NMR and high resolution mass spectrometry. ¹ H NMR (600MHz, CDCl ₃ ) δ7.53–7.50 (m, 2H), 7.33 (d, J=2.3Hz, 1H), 7.26 (m, 1H), 6.83–6.80 (m, 2H), 6.51 ( d, J=2.2Hz, 2H), 6.45(t, J=2.2Hz, 1H), 3.93(s, 3H), 3.80(s, 3H), 3.71(s, 6H); ¹³ C NMR (151MHz, CDCl ₃ )δ170.13,160.77,159.64,156.89,155.30,151.90,136.28,128.25,124.01,122.99,122.31,115.97,113.85,113.01,108.04,100.09,56.06,55.37,55.27；HRMS(ESI)calcdfor C ₂₅ H ₂₂ O ₇ [MH] ^- 433.1293, found 433.1292. The hydrogen spectrum of the product is shown in Figure 11. This product can be converted into the biologically active natural product diptoindonesin G through a two-step reaction by the method reported in the literature, and can also be used to synthesize other benzofuran natural products and their analogs (Singh DK, Kim IJOrg.Chem.2018, 83, 1667; Vo DD, Elofsson M. Adv. Synth. Catal. 2016, 358, 4085; Kim I., Choi J. Org. Biomol. Chem. 2009, 7, 2788.).

It remains in the mother liquor during recrystallization, and the more polar one is 2-(3,5-dimethoxyphenyl)-6-methoxy-3-(4-methoxyphenyl) when separated on a silica gel plate )-benzofuran-4-carboxylic acid, after drying, a white solid product (64.7 mg, yield 37%) was obtained. The structure of the obtained product was determined by H NMR, C NMR and high resolution mass spectrometry. ¹ H NMR (600MHz, CDCl ₃ ) δ7.35(d, J=2.4Hz, 1H), 7.28(d, J=2.4Hz, 1H), 7.27–7.25(m, 2H), 6.96–6.94(m, 2H), 6.73(d, J=2.3Hz, 2H), 6.37(t, J=2.3Hz, 1H), 3.94(s, 3H), 3.78(s, 3H), 3.63(s, 6H); ¹³ C NMR(151MHz,CDCl ₃ )δ170.90,160.61,159.20,157.35,155.46,151.68,132.24,131.36,126.71,124.44,122.82,118.02,114.03,113.72,104.53,101.44,100.26,56.17,55.45,55.32；HRMS(ESI ) calcd for C ₂₅ H ₂₂ O ₇ [MH] ^- 433.1293, found 433.1289.

Embodiment 35 (total synthesis of natural product diptoindonesin G)

With this technology as the key step, the natural product diptoindonesin G can be efficiently synthesized, and the following process is divided into three steps, and the synthetic route is shown in formula (4).

First, refer to Example 33 to synthesize the benzofuran-4-carboxylic acid intermediate. In a 10mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (4.9mg, 0.008mmol), 3-hydroxy-5-methoxybenzoic acid (80.7mg, 0.48 mmol), 1,3-dimethoxy-5-((4-methoxyphenyl)ethynyl)benzene (107.3mg, 0.40mmol), magnesium acetate tetrahydrate (21.4mg, 0.10mmol) and 0.5mL GVL, cover the upper opening of the reaction tube and leave the branch open to the air, then stir and react at 100°C for 20 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Petroleum ether and ethyl acetate were used as eluents to separate by silica gel column chromatography to obtain a solution containing two isomers, which was dried by rotary evaporation to obtain a crude product. The crude product was a mixture of two isomers, but without further separation, it was directly subjected to the next Friedel-Crafts reaction. The crude product was dissolved in 5.0 mL of anhydrous dichloromethane, and trifluoroacetic anhydride (140 μL, 1.0 mmol) was added. After stirring at room temperature for 12 h, 20 mL of methanol was added to quench the reaction, and the solvent and volatiles were removed by rotary evaporation. Using petroleum ether and ethyl acetate as the eluent, it was separated by silica gel column chromatography to obtain a yellow solid (73.5 mg, two-step yield 44%), which is tetramethyl-protected diptoindonesin G.

Finally, a demethylation reaction is performed. The above yellow solid (62.5 mg, 0.15 mmol) was dissolved in 3 mL of anhydrous dichloromethane, and boron tribromide solution (3.0 mL, 1.0 mol/L dichloromethane solution) was added at -78°C. Then the system was allowed to warm up to room temperature by itself, and after continuing the reaction for 16 h, ice water was added to quench the reaction. Filter the insoluble matter, wash it with water and dichloromethane successively, then dissolve it in a small amount of acetone, add petroleum ether, wash the separated precipitate with petroleum ether once, and drain it to obtain an orange-red solid (47.1mg, 87%) which is diptoindonesin g. The structure of the obtained product was determined by H NMR and C NMR spectra, and the characterization data were consistent with diptoindonesin G isolated from plants in the literature (Juliawaty LD, Sahidin, Hakim E.H., et al. Nat. Prod. Commun. 2009, 4, 947. ). ¹ H NMR (600MHz, acetone-d ₆ )δ14.24(s, 1H), 7.81(d, J=8.7Hz, 1H), 7.52(d, J=1.7Hz, 1H), 7.32(d, J= 1.7Hz, 1H), 7.30(d, J＝2.3Hz, 1H), 7.08(d, J＝8.7Hz, 1H), 6.35(d, J＝2.2Hz, 1H); ¹³ C NMR (151MHz, acetone- d ₆ ) δ 187.42, 168.17, 166.50, 160.95, 158.43, 157.38, 154.02, 135.55, 131.41, 126.23, 125.14, 122.09, 116.95, 111.55, 109.12, 108.14, 104.332, 104.338, 1 The hydrogen spectrum of the product is shown in Figure 12.

Embodiment 36 (gram scale synthesis)

In a 25mL reaction tube with a branch, add a magnetic stirrer, p-cymene dichloride ruthenium dimer (45.9mg, 0.075mmol), 3-hydroxy-5-methoxybenzoic acid (1.009g, 6.0 mmol), toluene (0.891g, 5.0mmol), magnesium acetate tetrahydrate (0.268g, 1.25mmol) and 4.0mL GVL, cover the upper opening of the reaction tube and leave its branch open to the air, and then in 100 ℃ The reaction was stirred for 24 hours. After the reaction was completed, ethyl acetate was added, filtered through a thin layer of diatomaceous earth, saturated sodium chloride solution was added, ethyl acetate extracted and separated, and the organic phase was dried with anhydrous sodium sulfate and concentrated. Using petroleum ether and ethyl acetate as the eluent, use silica gel column chromatography to separate, rotary evaporate and suck dry, and obtain a white solid (1.261g, yield 73%) which is the product 6-methoxy-2,3- Diphenylbenzofuran-4-carboxylic acid.

Comparative example 1

Refer to the synthesis conditions of benzofuran catalyzed by Pd in the literature (Kuram M.R., Bhanuchandra M., Sahoo A.K. Angew. Chem. Int. Ed. 2013, 52, 4607). A magnetic stirrer, tris(dibenzylideneacetone)dipalladium (9.2mg, 0.01mmol), 3-hydroxy-5-methylbenzoic acid (152.1mg, 1.0mmol), diphenyl Acetylene (35.6 mg, 0.20 mmol), sodium acetate (82.0 mg, 1.0 mmol), copper acetate monohydrate (40.0 mg, 0.40 mmol), and 2.0 mL of dioxane. The reaction tube was sealed and the reaction was stirred at 130°C for 48 hours. After the reaction was completed, ethyl acetate was added for dilution. Thin-layer chromatography analysis showed that a large amount of raw materials remained, and only a trace amount of product was generated. Gas chromatography-mass spectrometry analysis showed that the conversion rate of tolanylacetylene was less than 10%. Therefore, this Pd-catalyzed synthesis system is not suitable for the synthesis of diarylbenzofuran-4-carboxylic acid.

Comparative example 2

Refer to the synthesis conditions of Cu-catalyzed benzofuran in the literature (Zeng W., Wu W.Q., Jiang H.F., etal. Chem. Commun. 2013, 49, 6611.). A magnetic stirrer, copper trifluoromethanesulfonate (18.1mg, 0.05mmol), 3-hydroxy-5-methylbenzoic acid (114.1mg, 0.75mmol), toluene (89.1mg , 0.50mmol), zinc chloride (102.2mg, 0.75mmol) and 1.0mL nitrobenzene. The reaction tube was filled with oxygen, connected with an oxygen balloon, and stirred at 120° C. for 24 hours. After the reaction was completed, ethyl acetate was added for dilution, and thin-layer chromatographic analysis showed that a large amount of raw materials remained and no product was generated. Therefore, this Cu-catalyzed synthesis system is not suitable for the synthesis of diarylbenzofuran-4-carboxylic acid.

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included in the protection scope of the present invention.

Claims (12)

1. A method for preparing polysubstituted benzofuran-4-formic acid compounds under the catalysis of ruthenium is characterized by comprising the following preparation steps:

adding a m-hydroxybenzoic acid compound (I), diaryl alkyne (II), a ruthenium catalyst, an additive and a solvent into a reaction vessel, heating and stirring the mixture to react in an air or oxygen environment, separating and purifying a reaction crude product to obtain products (III) and (IV) of the polysubstituted benzofuran-4-formic acid, wherein the reaction formula is shown as formula (1):

wherein R is ¹ 、R ² And R ³ Each independently selected from hydrogen and C ₁ -C ₈ Alkyl radical, C ₆ -C ₁₀ Aryl radical, C ₁ -C ₈ One of alkoxy, benzyloxy, halogen, trifluoromethyl, hydroxyl, carboxyl and ester group; ar (Ar) ¹ And Ar ² Relatively independently represent a substituted or unsubstituted aryl group; when Ar is ² ＝Ar ¹ When the diaryl alkyne is a symmetric diaryl alkyne (V),obtaining a polysubstituted benzofuran-4-formic acid product (VI) with a reaction formula shown as a formula (2);

the ruthenium catalyst is at least one of a divalent ruthenium complex, a trivalent ruthenium complex, a divalent ruthenium salt and a trivalent ruthenium salt;

the additive is one of magnesium acetate tetrahydrate, anhydrous magnesium acetate, calcium acetate monohydrate, anhydrous calcium acetate, lithium acetate, sodium acetate, potassium acetate, guanidine carbonate and magnesium chloride;

the solvent is a polar aprotic solvent.

2. The method for preparing polysubstituted benzofuran-4-carboxylic acid compound according to claim 1, wherein said diaryl alkyne (II) has the following structure (VII):

wherein R is ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² And R ¹³ Each independently selected from hydrogen and C ₁ -C ₈ Alkyl radical, C ₆ -C ₁₀ Aryl radical, C ₁ -C ₈ Alkoxy, benzyloxy, halogen, trifluoromethyl, trifluoromethoxy and ester group.

3. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the ruthenium catalyst is one selected from p-cymene ruthenium dichloride dimer, phenyl ruthenium dichloride dimer, ruthenium trichloride, hydrated ruthenium trichloride, tris (triphenylphosphine) ruthenium dichloride and ruthenium acetate.

4. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 3, wherein: the ruthenium catalyst is p-cymene ruthenium dichloride dimer.

5. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the additive is magnesium acetate tetrahydrate.

6. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the solvent is gamma-valerolactone.

7. The method for preparing polysubstituted benzofuran-4-carboxylic acid compounds according to claim 1, which comprises the following steps: the molar ratio of the diaryl alkyne (II) to the m-hydroxybenzoic acid compound (I) is 1 (0.8-2).

8. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the molar usage of the catalyst is 1-10% of the molar usage of the diaryl alkyne (II) calculated by the usage of the contained metal ruthenium.

9. The method for preparing polysubstituted benzofuran-4-carboxylic acid compounds according to claim 1, which comprises the following steps: the molar dosage of the additive is 10-60% of the molar dosage of diaryl alkyne (II).

10. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the temperature of the heating and stirring reaction is 90-120 ℃, and the reaction time is 6-30 h.

11. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 1, wherein: the amount of the solvent is 0.5-5 mL per 1mmol of diaryl alkyne (II); and the separation and purification means that the obtained reaction liquid is cooled to room temperature, ethyl acetate is added for dilution, the reaction liquid is filtered through thin-layer diatomite, saturated sodium chloride or ammonium chloride solution and ethyl acetate are added for extraction, an organic phase is dried and concentrated, then silica gel column chromatography is used for separation, and rotary evaporation and pumping drying are carried out, so that a purified product is obtained.

12. The method for preparing the polysubstituted benzofuran-4-carboxylic acid compound by catalysis of ruthenium according to claim 11, wherein: the amount of solvent is 1-1.5 mL solvent per 1mmol diaryl alkyne (II).

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